Ischemia is a condition in which there is insufficient blood flow to a given part of the body to meet metabolic demand. This shortage of oxygen, glucose and other nutrients leads to tissue damage at the ischemic area. It can affect an entire organ, a limb or just a tissue part, depending of the vascular system involved. There are various types of ischemia with specific mechanisms, depending on the area experiencing the ischemic insult, but they all share overall processes responsible for such an insult with globally common consequences.
Many events can lead to an insufficient blood supply to a given tissue: atherosclerosis, thromboembolism, hypoglycemia, tachycardia, hypotension, outside compression of a blood vessel (e.g. by a tumor or following a trauma), embolism, sickle cell disease, localized extreme cold, tourniquet application, arteriovenous malformations, peripheral artery occlusive disease, hemorrhage.
One major consequence of ischemia is the lack of oxygen normally supplied through binding to hemoglobin in red blood cells. The affected tissue rapidly becomes hypoxic if not anoxic. This, added to the lack of glucose, the energy supply, leads to the release of proteolytic enzymes, reactive oxygen species and inflammatory mediators. This so-called ischemic cascade will ultimately cause cell death and tissue damage. Ischemia can thus develop in any part of the body, such as a limb, intestine, heart or brain. The heart and brain are among the organs that are the most quickly damaged by ischemia: necrosis becomes irreversible after only about 3-4 minutes after onset.
Cerebral ischemia is ischemia of the brain tissues resulting in loss of brain cells. Unlike other tissues which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur even during very brief periods of hypoxia or ischemia. At present, there is no effective neuroprotective strategy for the treatment of cerebral ischemia or hypoxia. Cerebrovascular disease is the third most common cause of death worldwide (WHO 2008), being responsible for 10.8% of worldwide deaths. In addition, it is one of the first causes of long-term disability in Western countries, with more than 50% of patients being left with a motor disability and a significant loss of quality-adjusted life years (QALY). The risk of cerebral ischemia increasing with age, the burden of cerebral ischemia is becoming greater as the population is aging. The improvement of health care by the development of faster and more effective therapy would therefore have an important medical and socioeconomic impact worldwide and is greatly needed.
Symptoms of cerebral ischemia and their severity vary greatly depending on the cerebral region(s) affected. For instance, they may include weakness in one entire side of the body, impairments in speech or vision and/or mental confusion. Focal cerebral ischemia, which occurs when a blood clot has occluded a cerebral vessel and is confined to a specific region of the brain, is usually caused by thrombosis or embolism. Global cerebral ischemia, which occurs when blood flow to the entire brain is stopped or drastically reduced, is commonly caused by cardiovascular disease. The area(s) of brain tissue affected as well as the delay in diagnosis and treatment are essential factors determining the outcome of cerebral ischemia, i.e., survival and level of disability after recovery.
One major consequence of cerebral ischemia is neuronal damage, which is mediated by the ischemic cascade that results in tissue damage leading to subsequent neuronal death and to disruption of the blood-brain barrier. It is estimated that 2 million brain cells die every minute after ischemic stroke onset. In addition, restoration of blood flow after a period of ischemia can actually be more damaging than the ischemia itself. The so-called reperfusion injury can result in acceleration of neuronal death.
There is, currently, no effective drug therapy to help patients during the acute phase of brain ischemia except thrombolysis and new endovascular devices or techniques which only a limited number of patients will benefit from. This is due to one major issue: a very narrow therapeutic window of less than 6 h from ischemia onset. Another major issue is the invasiveness and complexity of these procedures.
New therapies are currently contemplated which aim at (i) regenerating damaged brain areas to regain neurological function and (ii) targeting the ischemic cascade to minimize and even prevent brain damage. Unfortunately, so far, these new therapies have been effective in experimental settings but have failed translation to clinical practice.
Stimulation of neurogenesis using endogenous repair mechanisms such as neuronal progenitor cells or transplantation of stem cells is being actively investigated. Unfortunately, issues such as survival of the cells, proper differentiation and proper connectivity of the new neuronal cells remain unsolved so far (1).
Antioxidant enzymes, primarily superoxide dismutase (SOD), in association with catalase, and glutathione peroxidase, have been tested in vivo but showed no improvement in cerebral blood flow or neurological recovery (2).
Newer therapeutic approaches with different modes of action and a wider therapeutic window are currently being investigated for ischemic stroke: glutamate antagonists, anti-inflammatory agents, anti-apoptotic agents, and ion-channel modulators.
Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system. It activates glutamate receptors that are classified into three ionotropic classes (NMDA, AMPA and kainate receptors) and three metabotropic classes. Under normal conditions, glutamate concentration is maintained by glial and neuronal systems. During ischemia, an abnormally high concentration of extracellular glutamate is observed in the brain. Excessive accumulation of glutamate in synaptic clefts leads to the overactivation of glutamate receptors that results in pathological processes and finally in neuronal cell death. This process, named excitotoxicity, is commonly observed in neuronal tissues under ischemic conditions. From glutamate receptor overactivation ensues an accumulation in postsynaptic cells of several ion species, especially calcium (28). Overload of calcium is a key process of excitotoxicity. It results in deleterious cellular processes especially when specific structures such as mitochondria or endoplasmic reticula are no longer able to sequester cytoplasmic calcium. Excessive calcium overload in mitochondria is associated with the increased generation of reactive oxygen species as well as the release of proapoptotic mitochondrial proteins, which are both deleterious (28,29). Transient or sustained calcium influx into cells also activates a number of deleterious enzymes, including nitric oxide synthase, phospholipases, endonucleases, and proteases such as caspases and calpain (30).
Several glutamate receptor antagonists have been tested to counteract excitotoxicity. However, effects of glutamate receptor antagonists, such as the NMDA receptor antagonists Selfotel, Eliprodil and Aptiganel (Cerestat), could not be validated in clinical studies and several studies have been stopped (3). Dizolcipine (MK801), another NMDA receptor antagonist, is associated with numerous side effects. Calcium channel blockers such as Nimodipine and Flunarizine also showed no significant benefit versus placebo in clinical trials (4). A phase III trial with the AMPA receptor antagonist YM872 (zonampanel) is ongoing and seeks to determine its potential efficacy in combination with tPA thrombolysis.
A variety of anti-inflammatory drugs have been shown to reduce ischemic damage in animal studies. Commonly used anti-inflammatory agents are aspirin and the lipid-lowering statins. In addition, two leukocyte adhesion inhibitors, Enlimomab and LeukArrest, were studied in patients with ischemic stroke but secondary effects seemed to be greater than their therapeutic effects (5).
Ion channel modulators (i.e., Nimodipine, Fosphenytoin, Maxipost) failed at phase III due to a lack of demonstrated benefit (6).
Anti-apoptotic agents such as caspase inhibitors have been shown to reduce the area of ischemic damage in rodent stroke models (7). However, a recent study with erythropoietin yielded negative effects and raised safety concerns with an increased risk of death and further cerebrovascular events (8).
Due to the above-mentioned societal impact of cerebral ischemia, there is still a need for drugs effective in protecting neuronal cells during an ischemic or hypoxic event, following its onset, or in a preventive way in a patient at risk.